Repair of the damaged heart using cardiomyocytes derived from embryonic stem cells is a promising avenue for treatment of heart disease. Many fundamental questions about stem cell differentiation and cardiomyoplasty must be answered before that promise is realized in the clinic. We propose to develop a broadly applicable, cell based system to identify genetic factors involved in the directed differentiation of ES cells to cardiomyocytes. In Phase I we will determine the feasibility of this system by establishing a panel of ES cell lines from F2 embryos of one strain-pair, measuring the extent of differentiation to cardiomyocytes under defined culture conditions, and conducting a statistical analysis for quantitative trait loci (QTL) for differentiation to cardiomyocytes. The aim of Phase I is to demonstrate that the proposed ES cell panel can identify subchromosomal regions of the genome harboring one or more genes involved in differentiation of ES cells. In Phase II, F2 ES lines from additional strain-pairs will be established and, in conjunction with a panel of F1 ES cells, used to screen for genetic determinants of directed differentiation under a variety of culture conditions. The platform will be commercialized through strategic alliances with pharmaceutical and biotech companies, as well as in collaborations with academic institutions. PUBLIC HEALTH RELEVANCE: Over 13 million Americans are afflicted with coronary heart disease each year, leading to half a million deaths and healthcare costs in excess of fifty billion dollars. Using stem cells to repair the damaged heart is a promising new approach to treat a disease with very few treatment options. This project will aid in this approach by building a genetic system to identify the factors that influence production of heart cells from embryonic stem cells. [unreadable] [unreadable] [unreadable]